The invention relates to novel, pharmaceutically-active fused heterocyclic compounds and methods of using them to treat or prevent disorders and conditions mediated by the histamine H4 receptor.
Histamine was first identified as a hormone (Barger et al., J. Physiology 41:19-59, 1910) and has since been demonstrated to play a major role in a variety of physiological processes, including the inflammatory xe2x80x9ctriple responsexe2x80x9d via H1 receptors (Ash et al., Br. J. Pharmacology 27:427-439, 1966), gastric acid secretion via H2 receptors (Black et al., Nature 236:385-390, 1972), and neurotransmitter release in the central nervous system via H3 receptors (Arrang et al., Nature 302: 832-837, 1983) (for review see Hill et al., Pharmacol. Rev. 49: 253-278, 1997). All three histamine receptor subtypes have been demonstrated to be members of the superfamily of G-protein coupled receptors (Gantz et al., Proc. Natl. Acad. Sci. U.S.A. 88:429-433, 1991; Lovenberg et al., Mol. Pharmacol. 55:1101-1107, 1999; Yamashita et al., Proc. Natl. Acad. Sci. U.S.A. 88:11515-11519, 1991). There are, however, additional functions of histamine that have been reported, for which no receptor has been identified. For example, in 1994, Raible et al. demonstrated that histamine and R-xcex1-methylhistamine could activate calcium mobilization in human eosinophils (Raible et al., Am. J. Respir. Crit. Care Med. 149:1506-1511, 1994). These responses were blocked by the H3-receptor antagonist thioperamide. However, R-xcex1-methylhistamine was significantly less potent than histamine which was not consistent with the involvement of known H3 receptor subtypes. Therefore, Raible et al. hypothesized the existence of a novel histamine receptor on eosinophils that was non-H1, -H2, or -H3. Most recently several groups (Oda et al., J. Biol. Chem. 275(47):36781-36786, 2000; Liu et al., Mol. Pharmacol. 59:420-426, 2001; Nguyen et al., Mol. Pharmacol. 59:427-433, 2001; Zhu et al., Mol. Pharmacol. 59(3):434-441, 2001; Morse et al., J. Pharmacol. Exp. Ther. 296(3):1058-1066, 2001) have identified and characterized a fourth histamine receptor subtype, the H4 receptor. This receptor is a 390 amino-acid, seven-transmembrane G protein coupled receptor with approximately 40% homology to the histamine H3 receptor. In contrast to the H3 receptor, which is primarily located in the brain, the H4 receptor is expressed at greater levels in neutrophils and mast cells, among other cells, as reported by Morse et al. (see above).
Events that elicit the inflammatory response include physical stimulation (including trauma), chemical stimulation, infection, and invasion by a foreign body. The inflammatory response is characterized by pain, increased temperature, redness, swelling, reduced function, or a combination of these. Many conditions, such as allergies, asthma, chronic obstructed pulmonary disease (COPD), atherosclerosis, and autoimmune diseases, including rheumatoid arthritis and lupus, are characterized by excessive or prolonged inflammation. Inhibition of leukocyte recruitment can provide significant therapeutic value. Inflammatory diseases or inflammation-mediated diseases or conditions include, but are not limited to, acute inflammation, allergic inflammation, and chronic inflammation.
Mast cell de-granulation (exocytosis) leads to an inflammatory response that may be initially characterized by a histamine-modulated wheal and flare reaction. A wide variety of immunological (e.g., allergens or antibodies) and non-immunological (e.g., chemical) stimuli may cause the activation, recruitment, and de-granulation of mast cells. Mast cell activation initiates allergic (H1) inflammatory responses, which in turn cause the recruitment of other effector cells that further contribute to the inflammatory response. The histamine H2 receptors modulate gastric acid secretion, and the histamine H3 receptors affect neurotransmitter release in the central nervous system.
Examples of textbooks on the subject of inflammation include J. I. Gallin and R. Snyderman, Inflammation: Basic Principles and Clinical Correlates, 3rd Edition, (Lippincott Williams and Wilkins, Philadelphia, 1999); V. Stvrtinova, J. Jakubovsky and I. Hulin, xe2x80x9cInflammation and Feverxe2x80x9d, Pathophysiology Principles of Diseases (Textbook for Medical Students, Academic Press, 1995); Cecil et al., Textbook Of Medicine, 18th Edition (W. B. Saunders Company, 1988); and Steadmans Medical Dictionary.
A summary of the present invention follows.
The invention features a compound of formula (I) wherein: 
Wherein R1 is Ra, RaRbxe2x80x94, Raxe2x80x94Oxe2x80x94Rbxe2x80x94, or (Rc)(Rd)Nxe2x80x94Rbxe2x80x94, where Ra is H, cyano, xe2x80x94(Cxe2x95x90O)N(Rc)(Rd), xe2x80x94C(xe2x95x90NH)(NH2), C1-10 alkyl, C3-8 alkenyl, C3-8 cycloalkyl, C2-5 heterocyclic radical, or phenyl; where Rb is C1-8 alkylene, C2-8 alkenylene, C3-8 cycloalkylene, bivalent C3-8 heterocyclic radical, or phenylene; and Rc and Rd are each independently H, C1-8 alkyl, C2-8 alkenyl, C3-8 cycloalkyl, or phenyl;
R2xe2x80x2 is H, methyl, ethyl, NRpRq, xe2x80x94(CO)NRpRq, xe2x80x94(CO)ORr, xe2x80x94CH2NRpRq, or CH2ORr; where Rp, Rq, and Rr are independently selected from C1-6 alkyl, C3-6 cycloalkyl, phenyl; (C3-6 cycloalkyl)(C1-2 alkylene), benzyl or phenethyl; or Rp and Rq taken together with the nitrogen to which they are attached, form a 4-7 membered heterocyclic ring with 0 or 1 additional heteroatoms selected from O, S, and N;
R3xe2x80x2 is H, methyl, ethyl, NRsRt, xe2x80x94(CO)NRsRt, xe2x80x94(CO)ORu, xe2x80x94CH2NRsRt, or CH2ORu; where Rs, Rt, and Ru are independently selected from C1-6 alkyl, C3-6 cycloalkyl, phenyl; (C3-6 cycloalkyl)(C1-2 alkylene), benzyl or phenethyl; or Rs and Rt taken together with the nitrogen to which they are attached, form a 4-7 membered heterocyclic ring with 0 or 1 additional heteroatoms selected from O, S, and N;
R5xe2x80x2 is methyl, ethyl, or H;
R6xe2x80x2 is methyl, ethyl, or H;
R7xe2x80x2 is methyl, ethyl, or H;
X4 is NR1 or S;
X1 is CR3;
R3 is F, Cl, Br, CHO, Rf, RfRgxe2x80x94, Rfxe2x80x94Oxe2x80x94Rgxe2x80x94, or (Rh)(Ri)Nxe2x80x94Rgxe2x80x94, where Rf is H, C1-6 alkyl, C2-6 alkenyl, C3-6 cycloalkyl, C2-5 heterocyclic radical, or phenyl; where Rg is C1-6 alkylene, C2-6 alkenylene, C3-6 cycloalkylene, bivalent C3-6 heterocyclic radical, or phenylene; and Rh and Ri are each independently H, C1-6 alkyl, C2-6 alkenyl, C3-6 cycloalkyl, or phenyl;
X2 is NRe or O, provided that X2 is NRe where X1 is N; Re is H or C1-6 alkyl;
X3 is N;
Z is xe2x95x90O or xe2x95x90S;
each of R4 and R6 is independently H, F, Cl, Br, I, COOH, OH, nitro, amino, cyano, C1-4 alkoxy, or C1-4 alkyl;
R5 is H, F, Cl, Br, I, (Cxe2x95x90O)Rj, OH, nitro, NRjRk, cyano, phenyl, xe2x80x94OCH2xe2x80x94Ph, C1-4 alkoxy, or C1-4 alkyl;
R7 is H, F, Cl, Br, I, (Cxe2x95x90O)Rm, OH, nitro, NRlRm, cyano, phenyl, xe2x80x94OCH2xe2x80x94Ph C1-4 alkoxy, or C1-4 alkyl;
wherein each of Rj, Rk, Rl, and Rm is independently selected from H, C1-6 alkyl, hydroxy, phenyl, benzyl, phenethyl, and C1-6 alkoxy;
each of the above hydrocarbyl (including alkyl, alkoxy, phenyl, benzyl, cycloalkyl, and so on) or heterocyclic groups being independently and optionally substituted with between 1 and 3 substituents selected from C1-3 alkyl, halo, hydroxy, amino, and C1-3 alkoxy;
wherein n is 0, 1, or 2; where n is 2, the moiety xe2x80x94(CHR5xe2x80x2)n=2xe2x80x94 is xe2x80x94(CHR5xe2x80x2xe2x80x94CHR7xe2x80x2)xe2x80x94 where CHR5xe2x80x2 is between CHR6xe2x80x2 and CHR7xe2x80x2;
provided at least one of R1, R2xe2x80x2, R3, R4, R5, R6, and R7 is other than H when Z is O;
and provided, where Z is O, n=1, and each of R4, R5, R6, R7, R2xe2x80x2, R3xe2x80x2, R5xe2x80x2, and R6xe2x80x2 is H, (or at least 7, 8, or 9 of these 10 limitations apply) then (a) where X2 is NH, then R1 is (i) not methyl, pyridyl, phenyl, or benzyl, or (ii) is selected from the disclosed possibilities, but not C1-2 alkyl and not a six-membered aryl or six-membered nitrogen-containing heteroaryl, or phenyl(C1-2 alkylene) (alternatively, provided, where Z is O, n=1, and X2 is NH, then at least two (or three) of R4, R5, R6, R7, R2xe2x80x2, R3xe2x80x2, R5xe2x80x2, and R6xe2x80x2 is other than H); and (b) where X2 is O, then R1 is not methyl;
and provided, where Z is O, X2 is NH, n=1, R1 is methyl, each of R4, R6, R7, R2xe2x80x2, R3xe2x80x2, R5xe2x80x2, and R6xe2x80x2 is H (or at least 7, 8, 9, or 10 of these 11 limitations apply), then R5 is (i) not methoxy, (ii) not methoxy, or ethoxy, (iii) not C1-4 alkoxy, or (iv) not methoxy or hydroxy;
or a pharmaceutically acceptable salt, ester, or amide thereof.
According to one aspect of the invention, the invention features compounds of the following formula (Ib): 
Wherein R1 is Ra, RaRbxe2x80x94, Raxe2x80x94Oxe2x80x94Rbxe2x80x94, or (Rc)(Rd)Nxe2x80x94Rbxe2x80x94, where Ra is H, C1-10 alkyl, C3-8 alkenyl, C3-8 cycloalkyl, C2-5 heterocyclic radical, or phenyl; where Rb is C1-8 alkylene, C3-8 alkenylene, C3-8 cycloalkylene, bivalent C3-8 heterocyclic radical, or phenylene; and Rc and Rd are each independently H, C1-8 alkyl, C3-8 alkenyl, C3-8 cycloalkyl, or phenyl;
R2 is ortho (like R2xe2x80x2 in formula (I)) or meta (like R3xe2x80x2 in formula (I)), and is methyl or H;
X1 is CR3;
R3 is F, Cl, Br, Rf, RfRgxe2x80x94, Rfxe2x80x94Oxe2x80x94Rgxe2x80x94, or (Rh)(Ri)Nxe2x80x94Rgxe2x80x94, where Rf is H, C1-6 alkyl, C2-6 alkenyl, C3-6 cycloalkyl, C2-5 heterocyclic radical, or phenyl; where Rg is C1-6 alkylene, C2-6 alkenylene, C3-6 cycloalkylene, bivalent C3-6 heterocyclic radical, or phenylene; and Rh and Ri are each independently H, C1-6 alkyl, C2-6 alkenyl, C3-6 cycloalkyl, or phenyl;
X2 is NRe or O, provided that X2 is NRe when X1 is N; Re is H or C1-6 alkyl;
X3 is N;
Z is xe2x95x90O or xe2x95x90S;
each of R4 and R6 is independently H, F, Cl, Br, I, COOH, OH, nitro, amino, cyano, C1-4 alkoxy, or C1-4 alkyl;
R5 is H, F, Cl, Br, I, (Cxe2x95x90O)Rj, OH, nitro, NRjRk, cyano, xe2x80x94OCH2xe2x80x94Ph, C1-4 alkoxy, or C1-4 alkyl;
R7 is H, F, Cl, Br, I, (Cxe2x95x90O)Rm, OH, nitro, NRlRm, cyano, C1-4 alkoxy, or C1-4 alkyl;
wherein each of Rj, Rk, Rl, and Rm is independently selected from H, C1-6 alkyl, hydroxy, and C1-6 alkoxy; and
each of the above hydrocarbyl or heterocyclic groups being independently and optionally substituted with between 1 and 3 substituents selected from C1-3 alkyl, halo, hydroxy, amino, and C1-3 alkoxy;
provided at least one of R1, R2, R3, R4, R5, R6, and R7 is other than H when Z is xe2x95x90O;
or a pharmaceutically acceptable salt, ester, or amide thereof.
The invention also features methods of making and using such compounds in pharmaceutical composition, packaged drugs, and in the treatment or prevention of H4-mediated diseases and conditions, particularly those wherein it is desirable to antagonize the H4 receptor. For example, the expression of the H4 receptor in immune cells, including some leukocytes and mast cells, establishes it as an important target for therapeutic intervention in a range of immunological and inflammatory disorders (such as allergic, chronic, or acute inflammation). Specifically H4 receptor ligands are expected to be useful for the treatment or prevention of various mammalian disease states. Examples include: inflammatory disorders (such as those mediated by leukocytes or mast cells), asthma, psoriasis, rheumatoid arthritis, ulcerative colitis, Crohn""s disease, inflammatory bowel disease, multiple sclerosis, allergic disorders, autoimmune disease, lymphatic disorders, atherosclerosis, and immunodeficiency disorders.
In addition, H4 receptor ligands may be useful as adjuvants to chemotherapy. In the above methods of treatment, the invention also includes using compounds described in formula (I) and (Ib) without the provisos such as xe2x80x9cprovided at least one of R1, R2, R3, R4, R5, R6, and R7 is other than H when Z is Oxe2x80x9d above in pharmaceutical compositions for treating H4-mediated conditions, and in methods of treatment of H4-mediated diseases. Such a compound is, for example, Example 4.
Important synthetic intermediates of the above compounds include those wherein one or more of R4, R5, R6 and R7 is Br, I, cyano, nitro, alkoxy, or xe2x80x94OCH2Ph, which can be further modified to provide a wide range of substituents.
Other features and advantages of the invention will be apparent in the following detailed description, examples, and the appended claims.
The invention features compounds of formulae (I) and (Ib), methods of making them, and methods of using them in the preparation of pharmaceutical compositions for the treatment or prevention of H4-mediated diseases and conditions.
A. Terms
The following terms are defined below, and by their usage throughout the disclosure.
xe2x80x9cAlkylxe2x80x9d includes straight chain and branched hydrocarbons with at least one hydrogen removed to form a radical group. Alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, 1-methylpropyl, pentyl, isopentyl, sec-pentyl, hexyl, heptyl, octyl, and so on. Alkyl does not include cycloalkyl.
xe2x80x9cAlkenylxe2x80x9d includes straight chain and branched hydrocarbon radicals as above with at least one carbon-carbon double bond (sp2). Alkenyls include ethenyl (or vinyl), prop-1-enyl, prop-2-enyl (or allyl), isopropenyl (or 1-methylvinyl), but-1-enyl, but-2-enyl, butadienyls, pentenyls, hexa-2,4-dienyl, and so on. Hydrocarbon radicals having a mixture of double bonds and triple bonds, such as 2-penten-4-ynyl, are grouped as alkynyls herein. Alkenyl does not include cycloalkenyl.
xe2x80x9cAlkynylxe2x80x9d include straight chain and branched hydrocarbon radicals as above with at least one carbon-carbon triple bond (sp). Alkynyls include ethynyl, propynyls, butynyls, and pentynyls. Hydrocarbon radicals having a mixture of double bonds and triple bonds, such as 2-penten-4-ynyl, are grouped as alkynyls herein. Alkynyl does not include cycloalkynyl.
xe2x80x9cAlkoxyxe2x80x9d includes a straight chain or branched alkyl group with a terminal oxygen linking the alkyl group to the rest of the molecule. Alkoxy includes methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy, pentoxy and so on. xe2x80x9cAminoalkylxe2x80x9d, xe2x80x9cthioalkylxe2x80x9d, and xe2x80x9csulfonylalkylxe2x80x9d are analogous to alkoxy, replacing the terminal oxygen atom of alkoxy with, respectively, NH (or NR), S, and SO2.
xe2x80x9cArylxe2x80x9d includes phenyl, naphthyl, biphenylyl, and so on.
xe2x80x9cCycloalkylxe2x80x9d includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and so on.
xe2x80x9cCycloalkenylxe2x80x9d includes cyclobutenyl, cyclobutadienyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, cyclohexatrienyl (phenyl), cycloheptenyl, and so on. xe2x80x9cCycloalkynylxe2x80x9d includes the analogous rings with one or more triple bonds.
xe2x80x9cHeterocyclic radicalsxe2x80x9d include aromatic and nonaromatic rings having carbon atoms and at least one heteroatom (O, S, N) or heteroatom moiety (SO2, CO, CONH, COO) in the ring. Unless otherwise indicated, a heterocyclic radical may have a valence connecting it to the rest of the molecule through a carbon atom, such as 3-furyl or 2-imidazolyl, or through a heteroatom, such as N-piperidyl or 1-pyrazolyl. Examples of heterocyclic radicals include thiazoylyl, furyl, pyranyl, isobenzofuranyl, pyrrolyl, imidazolyl, pyrazolyl, isothiazolyl, isoxazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolizinyl, isoindolyl, indolyl, indazolyl, purinyl, quinolyl, furazanyl, pyrrolidinyl, pyrrolinyl, imdazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidyl, piperazinyl, indolinyl, and morpholinyl. For example, preferred heterocyclic radicals for R8 include morpholinyl, piperazinyl, pyrrolidinyl, pyridyl, cyclohexylimino, cycloheptylimino,and more preferably, piperidyl.
xe2x80x9cHaloxe2x80x9d includes fluoro, chloro, bromo, and iodo, and preferably fluoro or chloro.
xe2x80x9cPatientxe2x80x9d or xe2x80x9csubjectxe2x80x9d includes mammals such as humans and animals (dogs, cats, horses, rats, rabbits, mice, non-human primates) in need of observation, experiment, treatment or prevention in connection with the relevant disease or condition. Preferably, the patient is a human.
xe2x80x9cCompositionxe2x80x9d includes a product comprising the specified ingredients in the specified amounts as well as any product that results directly or indirectly from combinations of the specified ingredients in the specified amounts.
Concerning the various radicals in this disclosure and in the claims, two general remarks are made. The first remark concerns valency. As with all hydrocarbon radicals (hydrocarbyl), whether saturated, unsaturated or aromatic, and whether or not cyclic, straight chain, or branched, and also similarly with all heterocyclic radicals, each radical includes substituted radicals of that type and monovalent, bivalent, and multivalent radicals as indicated by the context of the claims. Hydrocarbyl includes alkoxy, in that the alkyl portion of an alkoxy group may be substituted. The context will indicate that the substituent is an alkylene or hydrocarbon radical with at least two hydrogen atoms removed (bivalent) or more hydrogen atoms removed (multivalent). An example of a bivalent radical linking two parts of the molecule is Rb in formula (I), which can link N(Rc)(Rd) with the ring nitrogen atom of the rest of the molecule. Another example of a bivalent moiety is an alkylene or alkenylene.
Second, radicals or structure fragments as defined herein are understood to include substituted radicals or structure fragments. Using xe2x80x9calkylxe2x80x9d as an example, xe2x80x9calkylxe2x80x9d should be understood to include substituted alkyl having one or more substitutions, such as between 1 and 5, 1 and 3, or 2 and 4 substituents. The substituents may be the same (dihydroxy, dimethyl), similar (chlorofluoro), or different (chlorobenzyl- or aminomethyl-substituted). Examples of substituted alkyl include haloalkyl (such as fluoromethyl, chloromethyl, difluoromethyl, perchloromethyl, 2-bromoethyl, and 3-iodocyclopentyl), hydroxyalkyl, aminoalkyl, nitroalkyl, alkylalkyl, and so on. Preferred substitutions for Ra include methyl, methoxy, trifluoromethoxy, difluoromethoxy, fluoromethoxy, fluoromethyl, difluoromethyl, perfluoromethyl (trifluoromethyl), 1-fluoroethyl, 2-fluoroethyl, ethoxy, fluoroethoxy, fluoro, chloro, and bromo, and particularly methyl, fluoromethyl, perfluoro, trifluoromethoxy, difluoromethoxy, methoxy, and fluoro.
B. Compounds
The invention features compounds of formula (I) and (Ib). Preferred compounds include those wherein: (a) X1 is CR3; (b) X3 is N; (c) X2 is N; (d) R1 is H, methyl, or ethyl; (e) X2 is N and X1 is CR3; (f) X2 is O and X1 is CR3; (g) X2 is N and Z is O; (h) R7 is H or Cl; (i) R1 is methyl or ethyl; R3xe2x80x2 or R2xe2x80x2 is, or both are, H; (k) R3 is H or Cl; (l) each of R5 and R7 is independently selected from H, F, Cl, and Br; (m) R3 is Cl; (n) at least one of R5 and R7 is F, Cl, Br, or methyl; (o) R5, or R7, or both is (are independently selected from) H, F, Cl, or Br; (p) R3xe2x80x2 or R2xe2x80x2 is methyl where R1 is H; R3xe2x80x2 or R2xe2x80x2 is otherwise H; or (q) at least one of R5 and R7 is not H; or (r) combinations thereof.
Additional examples of preferred compounds or combinations of the above include those wherein:
(s) X3 is N; R3 is H or Cl; R5 is F, Cl, Br, or methyl; and R7 is H, F, Cl, or Br;
(t) R3 is H or Cl; R5 is F, Cl, Br, or methyl; and R7 is H, F, Cl, Br, or methyl;
(u) R2 is methyl where R1 is H; R2 is otherwise H; X1 is CR3; R3 is H, F, or Cl; X2 is NRe or O, provided that X2 is NRe where X1 is N; Re is H or C1-3 alkyl; Z is xe2x95x90O or xe2x95x90S; each of R4 and R6 is independently H, OH, C1-4 alkyl, C1-4 alkoxy, cyano, or amino; R5 is H, F, Cl, Br, (Cxe2x95x90O)Rj, OH, amino, cyano, C1-4 alkoxy, or C1-4 alkyl; R7 is H, F, Cl, Br, (Cxe2x95x90O)Rm, C1-4 alkyl, C1-4 alkoxy, cyano, or amino; and
(v) R3xe2x80x2 and R2xe2x80x2 is methyl or H; X1 is CR3; R3 is H, F, or Cl; X2 is NRe or O, provided that X2 is NRe where X1 is N; Re is H or C1-6 alkyl; Z is xe2x95x90O or xe2x95x90S; each of R4 and R6 is H; R5 is H, F, Cl, Br, methyl, ethyl, or propyl; and R7 is H, F, Cl, Br, or C1-4 alkyl.
Examples of compounds include: (4-Methyl-piperazin-1-yl)-(5-trifluoromethyl-1H-indol-2-yl)-methanone; (7-Amino-5-methyl-1H-indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone; (5-Amino-7-methyl-1H-indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone; (7-Amino-5-bromo-1H-indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone; (5-Amino-7-bromo-1H-indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone; (5-Fluoro-7-methyl-1H-indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone; (7-Fluoro-5-methyl-1H-indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone; (6-Bromo-5-hydroxy-1H-indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone; (5-Bromo-6-hydroxy-1H-indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone; (6-Bromo-7-hydroxy-1H-indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone; (4-Bromo-7-hydroxy-1H-indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone; (6-Bromo-7-methyl-1H-indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone; and (4-Bromo-7-methyl-1H-indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone.
Additional examples of compounds include: (5,7-Dichloro-1H-indol-2-yl)-piperazin-1-yl-methanone; (5,7-Difluoro-1H-indol-2-yl)-piperazin-1-yl-methanone; (5,7-Difluoro-1H-indol-2-yl)-(3-methyl-piperazin-1-yl)-methanone; (5,6-Difluoro-1H-indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone; (4,6-Difluoro-1H-indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone.
Further examples of compounds include: 1-(5-Chloro-1H-indole-2-carbonyl)-4-methyl-piperazine-2-carboxylic acid methyl ester; 4-(5-Chloro-1H-indole-2-carbonyl)-1-methyl-piperazine-2-carboxylic acid methyl ester; 4-(5-Chloro-1H-indole-2-carbonyl)-1-methyl-piperazine-2-carboxylic acid amide; 1-(5-Chloro-1H-indole-2-carbonyl)-4-methyl-piperazine-2-carboxylic acid amide; 4-(5-Chloro-1H-indole-2-carbonyl)-1-methyl-piperazine-2-carboxylic acid methylamide; 1-(5-Chloro-1H-indole-2-carbonyl)-4-methyl-piperazine-2-carboxylic acid methylamide; 4-(5-Chloro-1H-indole-2-carbonyl)-1-methyl-piperazine-2-carboxylic acid dimethylamide; 1-(5-Chloro-1H-indole-2-carbonyl)-4-methyl-piperazine-2-carboxylic acid dimethylamide; (5-Chloro-1H-indol-2-yl)-(3-hydroxymethyl-4-methyl-piperazin-1-yl)-methanone; (5-Chloro-1H-indol-2-yl)-(3-methoxymethyl-4-methyl-piperazin-1-yl)-methanone; (5-Chloro-1H-indol-2-yl)-(2-methoxymethyl-4-methyl-piperazin-1-yl)-methanone; (5-Chloro-1H-indol-2-yl)-(4-methyl-3-methylaminomethyl-piperazin-1-yl)-methanone; (5-Chloro-1H-indol-2-yl)-(4-methyl-2-methylaminomethyl-piperazin-1-yl)-methanone; (5-Chloro-1H-indol-2-yl)-(3-dimethylaminomethyl-4-methyl-piperazin-1-yl)-methanone; and (5-Chloro-1H-indol-2-yl)-(2-dimethylaminomethyl-4-methyl-piperazin-1-yl)-methanone.
Examples of preferred compounds include: (5-Chloro-1H-indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone; (5-Fluoro-1H-indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone; (5-Bromo-1H-indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone; (5-Methyl-1H-indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone; (5,7-Difluoro-1H-indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone; (7-Chloro-1H-indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone; (5,7-Dichloro-1H-indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone; and (3,5-Dichloro-1H-indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone. More preferred compounds in this group include (5-Chloro-1H-indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone; (5-Bromo-1H-indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone; (5-Methyl-1H-indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone; (5,7-Difluoro-1H-indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone; (5-Fluoro-1H-indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone; (7-Amino-1H-indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone; (7-Methyl-1H-indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone; and (5,7-Dichloro-1H-indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone.
Further examples of preferred compounds include (6-Chloro-1H-indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone; (1H-Indol-2-yl)-(3-methyl-piperazin-1-yl)-methanone; (7-Bromo-1H-indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone; (5-Bromo-benzofuran-2-yl)-(4-methyl-piperazin-1-yl)-methanone; and (1H-Indol-2-yl)-(4-methyl-piperazin-1-yl)-methanethione.
The most preferred compound is (5-Chloro-1H-indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone.
The disclosed compounds can be prepared according to the next section.
C. Synthesis
The disclosed compounds may be made by combinatorial or traditional organic synthetic methods, as outlined below in Schemes 1-12 and Chemical Examples 1-86, or by analogous reactions. 
Compounds of formula III may be prepared from the compounds of formula II using conventional methods of amide bond formation. For example the carboxyl group of compound II may be activated as an active ester, acid chloride, anhydride, mixed anhydride, carbonic mixed anhydride or the like and treated with an amine containing group to give a compound of formula III. For example the compound of formula II may be converted to the corresponding active ester upon treatment with 1-hydroxybenzotriazole in the presence of a carbodiimide for example dicyclohexylcarbodiimide or 1-ethyl-3-(3xe2x80x2-dimethyl-aminopropyl)-carbodiimide hydrochloride in the presence of a base such as triethylamine or N,N-diisopropylethylamine to give a compound of formula III. In a preferred embodiment the compound of formula II is treated with O-(7-azabenzotriazol-1-yl)-N,N,Nxe2x80x2,Nxe2x80x2-tetramethyluroniumhexafluoro-phosphate, (HATU) and 1-hydroxy-7-azabenzotriazole, (HOAT) and N,N-diisopropylethyl-amine in a solvent, for example DMF, THF or the like, together with an amine component IV to give a compound of formula III. In an additional preferred embodiment a compound of formula II may be treated with carbonyldiimidazole (CDI) in a solvent, for example THF, DMF, dichloromethane or the like, followed by an amine component IV to give a compound of formula III. 
Compounds of formula III may be prepared according to the Fischer-Indole synthesis, which involves the condensation of a phenylhydrazine with an aldehyde or ketone to give an intermediate hydrazone. Thus a compound of formula V may be condensed with ethylpyruvate, usually in the presence of an acid catalyst, for example sulfuric acid to afford a hydrazone of formula VI. Compounds of formula VI may be converted into indoles of formula VII upon treatment with a protic or Lewis acid, if required at elevated temperature, to effect cyclisation. Examples of acids include; polyphosphoric acid, para-toluenesulfonic acid, pyridine hydrochloride, zinc chloride, phosphorus trichloride, polyphosphoric acid trimethylsilyl ester and acetic acid. Compound VI may also be converted to compound VII under thermal conditions by heating a compound of formula VI in a solvent, for example ethylene glycol, tetralin, or the like at elevated temperature, for example at about 150 to 250xc2x0 C. It will be recognized by one skilled in the art that cyclization of compounds of formula VI to compounds of formula VII can give rise to isomers when compounds of formula V contain substituents. It will be further recognized that the conditions to effect cyclization may be different for different compounds of formula VI.
In a further embodiment, compounds of formula VII may be prepared by condensing an appropriately substituted 2-nitrotoluene with an oxalate di-ester in the presence of a base followed by reduction of the intermediate to afford a compound of formula VII. In a preferred embodiment, a 2-nitrotoluene is condensed with ethylpyruvate in the presence of a base such as sodium methoxide, sodium butoxide, or sodium ethoxide in a solvent such as ethanol, methanol, or butanol. For example, a solution of 2-nitrotoluene in ethanol is heated with ethylpyruvate in the presence of sodium ethoxide at reflux temperature. The condensation product may be converted to a compound of formula VII using a reducing agent, preferably zinc in aqueous acetic acid. Compounds of formula VII may be converted to compounds of formula II using standard methods for ester hydrolysis, for example upon treatment with aqueous acid or base, if necessary at elevated temperature. In a preferred embodiment hydrolysis may be effected upon treating a compound of formula VII with a solution of lithium hydroxide in an alcoholic solvent, preferably ethanol. Compounds of formula II may be converted to compounds of formula III according to the procedures described previously. 
Compounds of formula IX may be prepared from the compounds of formula VIII using conventional methods of amide bond formation as described for the preparation of compounds of formula III from compounds of formula II by condensing the appropriate carboxylic acid of formula VIII with an amine component IV. 
Compounds of formula III may also be prepared as depicted in Scheme 4. Treatment of an optionally substituted 2-nitrotoluene (formula X) with an oxalate, such as diethyl oxalate, in the presence of a base affords a 2-keto ester of formula XI. Typical bases used to effect this transformation include potassium ethoxide, sodium hydride, and lithium t-butoxide. Reduction of the nitro group of a compound of formula XI to the corresponding aniline is accompanied by cyclization to the indole 2-carboxylate, a compound of formula VII. Typical reducants for this transformation include hydrogen over palladium, tin(II) chloride, and sulfur. Compounds of formula VII may be converted to compounds of formula II using standard methods for ester hydrolysis, for example upon treatment with aqueous acid or base, if necessary at elevated temperature. In a preferred embodiment hydrolysis may be effected upon treating a compound of formula VII with a solution of lithium hydroxide in THF. Conversion to the target compounds III is effected as described in Scheme 2.
Formulae XII and XIII do not exist in this disclosure. 
Compounds of formula III may be also be prepared from compounds of formula II by condensing a piperazine-1-carboxylic acid tert-butyl ester of formula XIV with a compound of formula II using conventional methods of amide bond formation as described for the preparation of compounds of formula III from compounds of formula II. In a preferred embodiment a compound of formula II is treated with carbonyldiimidazole (CDI) in a solvent, for example THF, DMF, dichloromethane or the like, followed a piperazine-1-carboxylic acid tert-butyl ester of formula XIV to afford a compound of formula XV. Compound XV may be converted to a compound of formula XVI upon treatment with an acid, for example trifluoroacetic acid or hydrochloric acid in a solvent, for example dichloromethane, THF, dioxane or the like. In a preferred embodiment the acid is trifluoroacetic acid and the solvent dichloromethane. A compound of formula III may be obtained from a compound of formula XVI upon treatment with an alkylating agent in the presence of a base. Suitable alkylating agents include, alkylbromides, alkylchlorides, alkyliodides, alkylmesylates, and alkyltosylates. This transformation is effected in the presence of a base, for example potassium carbonate, sodium hydroxide, triethylamine and the like, in a solvent, for example ethanol, methanol, acetone, dichloromethane, DMF, THF and the like. Preferred conditions use potassium carbonate in acetone. The reaction may be carried out at elevated temperature, preferably at about 50xc2x0 C. 
Compounds of formula XVIII may be prepared from compounds of formula XVII according to known methods for the functionalization of the indole nucleus at C-3. Such methods include, but are not limited to; halogenation, for example treatment with a halogen source in a solvent, for example upon treatment with bromine in acetic acid, N-chlorosuccinamide, N-bromosuccinamide, N-iodosuccinamide in dichloromethane, carbontetrachloride, chloroform or the like; formylation, for example by heating a DMF solution of a compound of formula XVII with phosphorus oxychloride (Vilsmeier-Haack conditions); aminoalkylation, for example by treating a compound of formula XVII with a mixture of am amine and a source of formaldehyde (Mannich conditions). One skilled in the art will recognize that not all reactions of indoles with electrophiles will lead to substitution at C-3 alone and that additional substitution may also take place and that mixtures of products may be obtained. It may be further recognized that the products of the substitution reactions (3-substituted indoles) may be used for further transformations. 
A compound of formula XX may be obtained from a compound of formula XIX upon treatment with 2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane-2,4-disulfide (also known as Lawesson""s reagent) in a solvent for example ether, THF or dioxane. In a preferred embodiment the compound of formula XIX is treated with Lawessons""s reagent in THF at ambient temperature to give a compound of formula XX. 
A compound of formula XXI may be obtained from a compound of formula XIX using conventional methods for amide bond reduction. For example using lithium aluminum hydride in THF, magnesium aluminum hydride in THF, lithium trimethoxyaluminum hydride, sodium bis(2-methoxyethoxy)-aluminum hydride, alane in THF and borane or borane-dimethyl sulfide complex in THF. A preferred method is the use of lithium aluminum hydride in a solvent, for example THF, dioxane, ether or the like at from 25xc2x0 C. to the boiling point of the selected solvent. In a more preferred embodiment the reducing agent is lithium aluminum hydride in THF at reflux temperature. As shown in the scheme below, compounds of formula XI may be prepared by utilizing a Phillips-type reaction that involves the condensation of an ortho-arylene diamine with a carboxcylic acid or the like, to generate the benzimidazole core. Accordingly, a compound of formula XXII may be 
condensed with glycolic acid and typically with an acid catalyst, for example hydrochloric acid, to afford compounds of formula XXIII. It will be recognized by one skilled in the art that the condensation of compounds of formula XXII to compounds of formula XXIII can give rise to isomers when compounds of formula XXII contain substituents. Compounds of formula XXIII may be oxidized with a suitable oxidizing agent to give compounds of formula X. Oxidants may include potassium permanganate, chromium trioxide, sodium hypochlorite, dimethyl sulfoxide with oxalyl chloride, manganese dioxide or any combination thereof. Compounds of formula X may be converted to compounds of formula XI according to the procedures described previously for compounds of formula II by condensing the appropriate carboxylic acid of formula X with an amine component IV. 
Scheme 10 illustrates methods of making substituted proximal and distal regioisomers. Analogous methods may be used with rings of other than 6 members, such as 5- or 7-membered rings. Further modifications may be made to change the hydroxymethyl and the methyl ester substituents using methods well known to those skilled in the art, including, but not limited to, those methods detailed in Schemes 11 and 12. Piperazine-1,2,4-tricarboxylic acid 1-benzyl ester 4-tert-butyl ester 2-methyl ester can be prepared according to the procedure of Bigge et al. (Tetrahedron Lett. 30:5193-5196, 1989). Selective deprotection of either the CBz or the BOC group can be accomplished using standard methods. For example, selective removal of the CBz group of piperazine-1,2,4-tricarboxylic acid 1-benzyl ester 4-tert-butyl ester 2-methyl ester can be accomplished upon treatment with, but not limited to, H2 and Pd/C or ammonium formate and Pd/C in solvents such as ethanol or ethyl acetate or the like, to give piperazine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester. Conversion of piperazine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester to 4-methyl-piperazine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester can be accomplished using standard conditions for reductive amination. These include, but are not limited to, treatment with paraformaldehyde in the presence of a reducing agent such as sodium borohydride, sodium cyanoborohydride or sodium triacetoxyborohydride or the like, in a solvent such as tetrahydrofuran, methanol, ethanol, 1,2-dichloroethane, trifluoroethanol, or the like. One skilled in the art will recognize that addition of acid to decrease the pH of the reaction mixture to a pH of less than about 7 may be necessary to effect reaction, wherein the acid is added as needed and is such as acetic acid, hydrochloric acid, and the like. Preferred reducing agents are sodium cyanoborohydride or sodium triacetoxyborohydride. Removal the the BOC group can be accomplished upon treatment with an acid, for example trifluoroacetic acid or hydrochloric acid in a solvent, for example dichloromethane, THF, dioxane or the like to give 1-methyl-piperazine-2-carboxylic acid methyl ester. Reduction of the methyl ester can be accomplished using standard conditions including, but not limited to, treatment with reducing agents such as lithium aluminum hydride or diisobutylaluminum hydride or the like, in solvents such as THF or diethyl ether or the like to afford (1-methyl-piperazin-2-yl)-methanol.
Alternatively, selective removal of the BOC group of piperazine-1,2,4-tricarboxylic acid 1-benzyl ester 4-tert-butyl ester 2-methyl ester can be accomplished upon treatment with an acid, for example trifluoroacetic acid or hydrochloric acid in a solvent, for example dichloromethane, THF, dioxane or the like to give piperazine-1,2-dicarboxylic acid 1-benzyl ester 2-methyl ester. Conversion of piperazine-1,2-dicarboxylic acid 1-benzyl ester 2-methyl ester to 4-methyl-piperazine-1,2-dicarboxylic acid 1-benzyl ester 2-methyl ester can be accomplished using standard conditions for reductive amination. These include, but are not limited to, treatment with paraformaldehyde in the presence of a reducing agent such as sodium borohydride, sodium cyanoborohydride or sodium triacetoxyborohydride, or the like, in a solvent such as tetrahydrofuran, methanol, ethanol, 1,2-dichloroethane, trifluoroethanol, or the like. One skilled in the art will recognize that addition of acid to decrease the pH of the reaction mixture to a pH of less than about 7 may be necessary to effect reaction, wherein the acid is added as needed and is such as acetic acid, hydrochloric acid, or the like. Preferred reducing agents are sodium cyanoborohydride or sodium triacetoxyborohydride. Removal of the CBz group of 4-methyl-piperazine-1,2-dicarboxylic acid 1-benzyl ester 2-methyl ester can be accomplished upon treatment with, but not limited to, H2 and Pd/C or ammonium formate and Pd/C in sovents such as ethanol or ethyl acetate or the like, to give 4-methyl-piperazine-2-carboxylic acid methyl ester. Reduction of the methyl ester can be accomplished using standard conditions including, but not limited, to treatment with reducing agents such as lithium aluminum hydride or diisobutylaluminum hydride or the like, in solvents such as THF or diethyl ether or the like, to afford (4-methyl-piperazin-2-yl)-methanol. 
Compounds of formulas XXIV and XXVII may be prepared from compounds of formula II using conventional methods of amide bond formation, as described for the preparation of compounds of formula III from compounds of formula II, by condensing the appropriate carboxylic acid of formula II with an amine component such as those described in Scheme 10. Schemes 11 and 12 illustrate non-limiting methods for providing the substituted rings, such as the substituted piperazines shown in compounds XXVI and XXIX. For Scheme 11, hydrolysis of the ester can be accomplished using standard methods for ester hydrolysis, for example upon treatment with aqueous acid or base, if necessary at elevated temperature. Compounds of formula XXVI where Y is nitrogen can be prepared using conventional methods of amide bond formation, as described for the preparation of compounds of formula III from compounds of formula II, by condensing the appropriate carboxylic acid of formula XXV with a suitable amine component. Compounds of formula XXVI where Y is oxygen can be prepared using conventional methods of ester formation such as, but not limited to, conversion to the acid chloride using reagents such as oxalyl chloride, or the like, followed by treatment with an appropriate alcohol. For Scheme 12, compounds of formula XXVIII can be prepared from compounds of formula XXVII using conventional methods such as, but not limited to, treatment with triphenylphosphine and carbon tetrabromide, thionyl bromide or HBr. Compounds of formula XXVIII may be treated with alcohols or amines to afford compounds of formula XXIX where Y is oxygen or nitrogen respectively, possibly in the presense of a suitable base such as, but not limited to, cesium carbonate or triethylamine.
D. Uses
According to the invention, the disclosed compounds and compositions are useful for the amelioration of symptoms associated with, the treatment of, and the prevention of, the following conditions and diseases: inflammatory disorders, asthma, atherosclerosis, psoriasis, rheumatoid arthritis, ulcerative colitis, Crohn""s disease, inflammatory bowel disease, multiple sclerosis, allergic disorders, dermatological disorders, autoimmune disease, lymphatic disorders, and immunodeficiency disorders. The disclosed compounds may also be useful as adjuvants in chemotherapy or in the treatment of itchy skin. The invention also features pharmaceutical compositions that include, without limitation, one or more of the disclosed compounds, and pharmaceutically acceptable carrier or excipient.
Aspects of the invention include (a) a pharmaceutical composition comprising a compound of formula (I) or (Ib), or one or more preferred compounds as described herein, and a pharmaceutically acceptable carrier; (b) a packaged drug comprising (1) a pharmaceutical composition comprising a compound of claim 1, 2, or 3 and a pharmaceutically acceptable carrier, and (2) instructions for the administration of said composition for the treatment or prevention of an H4-mediated disease or condition.
The invention also provides a method for treating an H4-mediated condition in a patient, said method comprising administering to the patient a pharmaceutically effective amount of a composition comprising a compound of formula (I) or (Ib) or other disclosed or preferred compounds. For example, the invention features a method for treating an H4 mediated condition in a patient, said method comprising administering to the patient a pharmaceutically effective H4-antagonizing amount of a composition comprising a compound of formula (I) or (Ib) or other disclosed or preferred compounds.
The effect of an antagonist may also be produced by an inverse agonist. Inverse agonism describes the property of a compound to actively turn off a receptor that displays constitutive activity. Constitutive activity can be identified in cells that have been forced to over-express the human H4 receptor. Constitutive activity can be measured by examining cAMP levels or by measuring a reporter gene sensitive to cAMP levels after a treatment with a cAMP-stimulating agent such as forskolin. Cells that over-express H4 receptors will display lower cAMP levels after forskolin treatment than non-expressing cells. Compounds that behave as H4 agonists will dose-dependently lower forskolin-stimulated cAMP levels in H4-expressing cells. Compounds that behave as inverse H4 agonists will dose-dependently stimulate cAMP levels in H4-expressing cells. Compounds that behave as H4 antagonists will block either H4 agonist-induced inhibition of cAMP or inverse H4 agonist-induced increases in cAMP.
Further embodiments of the invention include disclosed compounds that are inhibitors of a mammalian histamine H4 receptor function, inhibitors of inflammation or inflammatory responses in vivo or in vitro, modulators of the expression of a mammalian histamine H4 receptor protein, inhibitors of polymorphonuclear leukocyte activation in vivo or in vitro, or combinations of the above, and corresponding methods of treatment, prophylaxis, and diagnosis comprising the use of a disclosed compound.
1. Dosages
Those skilled in the art will be able to determine, according to known methods, the appropriate dosage for a patient, taking into account factors such as age, weight, general health, the type of symptoms requiring treatment, and the presence of other medications. In general, an effective amount will be between 0.01 and 1000 mg/kg per day, preferably between 0.5 and 300 mg/kg body weight, and daily dosages will be between 10 and 5000 mg for an adult subject of normal weight. Capsules, tablets or other formulations (such as liquids and film-coated tablets) may be of between 0.5 and 200 mg, such as 1, 3, 5, 10, 15, 25, 35, 50 mg, 60 mg, and 100 mg and can be administered according to the disclosed methods.
2. Formulations
Dosage unit forms include tablets, capsules, pills, powders, granules, aqueous and nonaqueous oral solutions and suspensions, and parenteral solutions packaged in containers adapted for subdivision into individual doses. Dosage unit forms can also be adapted for various methods of administration, including controlled release formulations, such as subcutaneous implants. Administration methods include oral, rectal, parenteral (intravenous, intramuscular, subcutaneous), intracisternal, intravaginal, intraperitoneal, intravesical, local (drops, powders, ointments, gels or cream), and by inhalation (a buccal or nasal spray).
Parenteral formulations include pharmaceutically acceptable aqueous or nonaqueous solutions, dispersion, suspensions, emulsions, and sterile powders for the preparation thereof. Examples of carriers include water, ethanol, polyols (propylene glycol, polyethylene glycol), vegetable oils, and injectable organic esters such as ethyl oleate. Fluidity can be maintained by the use of a coating such as lecithin, a surfactant, or maintaining appropriate particle size. Carriers for solid dosage forms include (a) fillers or extenders, (b) binders, (c) humectants, (d) disintegrating agents, (e) solution retarders, (f) absorption accelerators, (g) adsorbants, (h) lubricants, (i) buffering agents, and (j) propellants.
Compositions may also contain adjuvants such as preserving, wetting, emulsifying, and dispensing agents; antimicrobial agents such as parabens, chlorobutanol, phenol, and sorbic acid; isotonic agents such as a sugar or sodium chloride; absorption-prolonging agents such as aluminum monostearate and gelatin; and absorption-enhancing agents.
3. Related Compounds
The invention provides the disclosed compounds and closely related, pharmaceutically acceptable forms of the disclosed compounds, such as salts, esters, amides, hydrates or solvated forms thereof; masked or protected forms; and racemic mixtures, or enantiomerically or optically pure forms.
Pharmaceutically acceptable salts, esters, and amides include carboxylate salts (e.g., C1-8 alkyl, cycloalkyl, aryl, heteroaryl, or non-aromatic heterocyclic) amino acid addition salts, esters, and amides that are within a reasonable benefit/risk ratio, pharmacologically effective and suitable for contact with the tissues of patients without undue toxicity, irritation, or allergic response. Representative salts include hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, lactiobionate, and laurylsulfonate. These may include alkali metal and alkali earth cations such as sodium, potassium, calcium, and magnesium, as well as non-toxic ammonium, quaternary ammonium, and amine cations such as tetramethyl ammonium, methylamine, trimethylamine, and ethylamine. See example, S. M. Berge, et al., xe2x80x9cPharmaceutical Salts,xe2x80x9d J. Pharm. Sci., 1977, 66:1-19, which is incorporated herein by reference. Representative pharmaceutically acceptable amides of the invention include those derived from ammonia, primary C1-6 alkyl amines and secondary di (C1-6 alkyl) amines. Secondary amines include 5- or 6-membered heterocyclic or heteroaromatic ring moieties containing at least one nitrogen atom and optionally between 1 and 2 additional heteroatoms. Preferred amides are derived from ammonia, C1-3 alkyl primary amines, and di (C1-2 alkyl)amines. Representative pharmaceutically acceptable esters of the invention include C1-7 alkyl, C5-7 cycloalkyl, phenyl, and phenyl(C1-6)alkyl esters. Preferred esters include methyl esters.
The invention also includes disclosed compounds having one or more functional groups (e.g., hydroxyl, amino, or carboxyl) masked by a protecting group. Some of these masked or protected compounds are pharmaceutically acceptable; others will be useful as intermediates. Synthetic intermediates and processes disclosed herein, and minor modifications thereof, are also within the scope of the invention.
Hydroxyl Protecting Groups
Protection for the hydroxyl group includes methyl ethers, substituted methyl ethers, substituted ethyl ethers, substitute benzyl ethers, and silyl ethers.
Substituted Methyl Ethers
Examples of substituted methyl ethers include methyoxymethyl, methylthiomethyl, t-butylthiomethyl, (phenyldimethylsilyl)methoxymethyl, benzyloxymethyl, p-methoxybenzyloxymethyl, (4-methoxyphenoxy)methyl, guaiacolmethyl, t-butoxymethyl, 4-pentenyloxymethyl, siloxymethyl, 2-methoxyethoxymethyl, 2,2,2-trichloroethoxymethyl, bis(2-chloroethoxy)methyl, 2-(trimethylsilyl)ethoxymethyl, tetrahydropyranyl, 3-bromotetrahydropyranyl, tetrahydrothiopyranyl, 1-methoxycyclohexyl, 4-methoxytetrahydropyranyl, 4-methoxytetrahydrothiopyranyl, 4-methoxytetrahydrothiopyranyl S,S-dioxido, 1-[(2-chloro-4-methyl)phenyl]-4-methoxypiperidin-4-yl, 1,4-dioxan-2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl and 2,3,3a,4,5,6,7,7a-octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-yl.
Substituted Ethyl Ethers
Examples of substituted ethyl ethers include 1-ethoxyethyl, 1-(2-chloroethoxy)ethyl, 1-methyl-1-methoxyethyl, 1-methyl-1-benzyloxyethyl, 1-methyl-1-benzyloxy-2-fluoroethyl, 2,2,2-trichloroethyl, 2-trimethylsilylethyl, 2-(phenylselenyl)ethyl, t-butyl, allyl, p-chlorophenyl, p-methoxyphenyl, 2,4-dinitrophenyl, and benzyl.
Substituted Benzyl Ethers
Examples of substituted benzyl ethers include p-methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl, p-phenylbenzyl, 2- and 4-picolyl, 3-methyl-2-picolyl N-oxido, diphenylmethyl, p,pxe2x80x2-dinitrobenzhydryl, 5-dibenzosuberyl, triphenylmethyl, xcex1-naphthyldiphenylmethyl, p-methoxyphenyldiphenylmethyl, di(p-methoxyphenyl)phenylmethyl, tri(p-methoxyphenyl)methyl, 4-(4xe2x80x2-bromophenacyloxy)phenyldiphenylmethyl, 4,4xe2x80x2,4xe2x80x3-tris(4,5-dichlorophthalimidophenyl)methyl, 4,4xe2x80x2,4xe2x80x3-tris(levulinoyloxyphenyl)methyl, 4,4xe2x80x2,4xe2x80x3-tris(benzoyloxyphenyl)methyl, 3-(Imidazol-1-ylmethyl)bis(4xe2x80x2,4xe2x80x3-dimethoxyphenyl)methyl, 1,1-bis(4-methoxyphenyl)-1xe2x80x2-pyrenylmethyl, 9-anthryl, 9-(9-phenyl)xanthenyl, 9-(9-phenyl-10-oxo)anthryl, 1,3-benzodithiolan-2-yl, and benzisothiazolyl S,S-dioxido.
Silyl Ethers
Examples of silyl ethers include trimethylsilyl, triethylsilyl, triisopropylsilyl, dimethylisopropylsilyl, diethylisopropylsilyl, dimethylthexylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, tribenzylsilyl, tri-p-xylylsilyl, triphenylsilyl, diphenylmethylsilyl, and t-butylmethoxyphenylsilyl.
Esters
In addition to ethers, a hydroxyl group may be protected as an ester. Examples of esters include formate, benzoylformate, acetate, chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, phenoxyacetate, p-chlorophenoxyacetate, p-P-phenylacetate, 3-phenylpropionate, 4-oxopentanoate(levulinate), 4,4-(ethylenedithio)pentanoate, pivaloate, adamantoate, crotonate, 4-methoxycrotonate, benzoate, p-phenylbenzoate, 2,4,6-trimethylbenzoate(mesitoate)
Carbonates
Examples of carbonates include methyl, 9-fluorenylmethyl, ethyl, 2,2,2-trichloroethyl, 2-(trimethylsilyl)ethyl, 2-(phenylsulfonyl)ethyl, 2-(triphenylphosphonio)ethyl, isobutyl, vinyl, allyl, p-nitrophenyl, benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, S-benzyl thiocarbonate, 4-ethoxy-1-naphthyl, and methyl dithiocarbonate.
Assisted Cleavage
Examples of assisted cleavage include 2-iodobenzoate, 4-azidobutyrate, 4-nitro-4-methylpentanoate, o-(dibromomethyl)benzoate, 2-formylbenzenesulfonate, 2-(methylthiomethoxy)ethyl carbonate, 4-(methylthiomethoxy)butyrate, and 2-(methylthiomethoxymethyl)benzoate.
Miscellaneous Esters
Examples of miscellaneous esters include 2,6-dichloro-4-methylphenoxyacetate, 2,6-dichloro-4-(1,1,3,3-tetramethylbutyl)phenoxyacetate, 2,4-bis(1,1-dimethylpropyl)phenoxyacetate, chlorodiphenylacetate, isobutyrate, monosuccinoate, (E)-2-methyl-2-butenoate(tigloate), o-(methoxycarbonyl)benzoate, p-P-benzoate, xcex1-naphthoate, nitrate, alkyl N,N,Nxe2x80x2,Nxe2x80x2-tetramethylphosphorodiamidate, N-phenylcarbamate, borate, dimethylphosphinothioyl, and 2,4-dinitrophenylsulfenate
Sulfonates
Examples of sulfonates include sulfate, methanesulfonate(mesylate), benzylsulfonate, and tosylate.
Protection for 1,2- and 1,3-Diols
Cyclic Acetals and Ketals
Examples of cyclic acetals and ketals include methylene, ethylidene, 1-t-butylethylidene, 1-phenylethylidene, (4-methoxyphenyl)ethylidene, 2,2,2-trichloroethylidene, acetonide (isopropylidene), cyclopentylidene, cyclohexylidene, cycloheptylidene, benzylidene, p-methoxybenzylidene, 2,4-dimethoxybenzylidene, 3,4-dimethoxybenzylidene, and 2-nitrobenzylidene.
Cyclic Ortho Esters
Examples of cyclic ortho esters include methoxymethylene, ethoxymethylene, dimethoxymethylene, 1-methoxyethylidene, 1-ethoxyethylidine, 1,2-dimethoxyethylidene, xcex1-methoxybenzylidene, 1-(N,N-dimethylamino)ethylidene derivative, xcex1-(N,N-dimethylamino)benzylidene derivative, and 2-oxacyclopentylidene.
Silyl Derivatives
Examples of silyl derivatives include di-t-butylsilylene group, and 1,3-(1,1,3,3-tetraisopropyldisiloxanylidene) derivative.
Amino Protecting Groups
Protection for the amino group includes carbamates, amides, and special xe2x80x94NH protective groups.
Examples of carbamates include methyl and ethyl carbamates, substituted ethyl carbamates, assisted cleavage carbamates, photolytic cleavage carbamates, urea-type derivatives, and miscellaneous carbamates.
Carbamates
Examples of methyl and ethyl carbamates include methyl and ethyl, 9-fluorenylmethyl, 9-(2-sulfo)fluorenylmethyl, 9-(2,7-dibromo)fluorenylmethyl, 2,7-di-t-butyl-[9-(10,10-dioxo-10,10,10,10-tetrahydrothioxanthyl)]methyl, and 4-methoxyphenacyl.
Substituted Ethyl
Examples of substituted ethyl carbamates include 2,2,2-trichloroethyl, 2-trimethylsilylethyl, 2-phenylethyl, 1-(1-adamantyl)-1-methylethyl, 1,1-dimethyl-2-haloethyl, 1,1-dimethyl-2,2-dibromoethyl, 1,1-dimethyl-2,2,2-trichloroethyl, 1-methyl-1-(4-biphenylyl)ethyl, 1-(3,5-di-t-butylphenyl)-1-methylethyl, 2-(2xe2x80x2- and 4xe2x80x2-pyridyl)ethyl, 2-(N,N-dicyclohexylcarboxamido)ethyl, t-butyl, 1-adamantyl, vinyl, allyl, 1-isopropylallyl, cinnamyl, 4-nitrocinnamyl, 8-quinolyl, N-hydroxypiperidinyl, alkyldithio, benzyl, p-methoxybenzyl, p-nitrobenzyl, p-bromobenzyl, p-chlorobenzyl, 2,4-dichlorobenzyl, 4-methylsulfinylbenzyl, 9-anthrylmethyl and diphenylmethyl.
Assisted Cleavage
Examples of assisted cleavage include 2-methylthioethyl, 2-methylsulfonylethyl, 2-(p-toluenesulfonyl)ethyl, [2-(1,3-dithianyl)]methyl, 4-methylthiophenyl, 2,4-dimethylthiophenyl, 2-phosphonioethyl, 2-triphenylphosphonioisopropyl, 1,1-dimethyl-2-cyanoethyl, m-chloro-p-acyloxybenzyl, p-(dihydroxyboryl)benzyl, 5-benzisoxazolylmethyl, and 2-(trifluoromethyl)-6-chromonylmethyl.
Photolytic Cleavage
Examples of photolytic cleavage include m-nitrophenyl, 3,5-dimethoxybenzyl, o-nitrobenzyl, 3,4-dimethoxy-6-nitrobenzyl, and phenyl(o-nitrophenyl)methyl.
Urea-Type Derivatives
Examples of urea-type derivatives include phenothiazinyl-(10)-carbonyl derivative, Nxe2x80x2-p-toluenesulfonylaminocarbonyl, and Nxe2x80x2-phenylaminothiocarbonyl.
Miscellaneous Carbamates
Examples of miscellaneous carbamates include t-amyl, S-benzyl thiocarbamate, p-cyanobenzyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclopropylmethyl, p-decyloxybenzyl, diisopropylmethyl, 2,2-dimethoxycarbonylvinyl, o-(N,N-dimethylcarboxamido)benzyl, 1,1-dimethyl-3-(N,N-dimethylcarboxamido)propyl, 1,1-dimethylpropynyl, di(2-pyridyl)methyl, 2-furanylmethyl, 2-iodoethyl, isobornyl, isobutyl, isonicotinyl, p-(pxe2x80x2-methoxyphenylazo)benzyl, 1-methylcyclobutyl, 1-methylcyclohexyl, 1-methyl-1-cyclopropylmethyl, 1-methyl-1-(3,5-dimethoxyphenyl)ethyl, 1-methyl-1-(p-phenylazophenyl)ethyl, 1-methyl-1-phenylethyl, 1-methyl-1-(4-pyridyl)ethyl, phenyl, p-(phenylazo)benzyl, 2,4,6-tri-t-butylphenyl, 4-(trimethylammonium)benzyl, and 2,4,6-trimethylbenzyl.
Examples of Amides Include
Amides
N-formyl, N-acetyl, N-chloroacetyl, N-trichloroacetyl, N-trifluoroacetyl, N-phenylacetyl, N-3-phenylpropionyl, N-picolinoyl, N-3-pyridylcarboxamide, N-benzoylphenylalanyl derivative, N-benzoyl, N-p-phenylbenzoyl.
Assisted Cleavage
N-o-nitrophenylacetyl, N-o-nitrophenoxyacetyl, N-acetoacetyl, (Nxe2x80x2-dithiobenzyloxycarbonylamino)acetyl, N-3-(p-hydroxyphenyl)propionyl, N-3-(o-nitrophenyl)propionyl, N-2-methyl-2-(o-nitrophenoxy)propionyl, N-2-methyl-2-(o-phenylazophenoxy)propionyl, N-4-chlorobutyryl, N-3-methyl-3-nitrobutyryl, N-o-nitrocinnamoyl, N-acetylmethionine derivative, N-o-nitrobenzoyl, N-o-(benzoyloxymethyl)benzoyl, and 4,5-diphenyl-3-oxazolin-2-one.
Cyclic Imide Derivatives
N-phthalimide, N-dithiasuccinoyl, N-2,3-diphenylmaleoyl, N-2,5-dimethylpyrrolyl, N-1,1,4,4-tetramethyldisilylazacyclopentane adduct, 5-substituted 1,3-dimethyl-1,3,5-triazacyclohexan-2-one, 5-substituted 1,3-dibenzyl-1,3,5-triazacyclohexan-2-one, and 1-substituted 3,5-dinitro-4-pyridonyl.
Examples of Special NH Protective Groups Include
N-Alkyl and N-Aryl Amines
N-methyl, N-allyl, N-[2-(trimethylsilyl)ethoxy]methyl, N-3-acetoxypropyl, N-(1-isopropyl-4-nitro-2-oxo-3-pyrrolin-3-yl), quaternary ammonium salts, N-benzyl, N-di(4-methoxyphenyl)methyl, N-5-dibenzosuberyl, N-triphenylmethyl, N-(4-methoxyphenyl)diphenylmethyl, N-9-phenylfluorenyl, N-2,7-dichloro-9-fluorenylmethylene, N-ferrocenylmethyl, and N-2-picolylamine Nxe2x80x2-oxide.
Imine Derivatives
N-1,1-dimethylthiomethylene, N-benzylidene, N-p-methoxybenzylidene, N-diphenylmethylene, N-[(2-pyridyl)mesityl]methylene, and N-(Nxe2x80x2,Nxe2x80x2-dimethylaminomethylene).
Protection for the Carbonyl Group
Acyclic Acetals and Ketals
Examples of acyclic acetals and ketals include dimethyl, bis(2,2,2-trichloroethyl), dibenzyl, bis(2-nitrobenzyl) and diacetyl.
Cyclic Acetals and Ketals
Examples of cyclic acetals and ketals include 1,3-dioxanes, 5-methylene-1,3-dioxane, 5,5-dibromo-1,3-dioxane, 5-(2-pyridyl)-1,3-dioxane, 1,3-dioxolanes, 4-bromomethyl-1,3-dioxolane, 4-(3-butenyl)-1,3-dioxolane, 4-phenyl-1,3-dioxolane, 4-(2-nitrophenyl)-1,3-dioxolane, 4,5-dimethoxymethyl-1,3-dioxolane, O,Oxe2x80x2-phenylenedioxy and 1,5-dihydro-3H-2,4-benzodioxepin.
Acyclic Dithio Acetals and Ketals
Examples of acyclic dithio acetals and ketals include S,Sxe2x80x2-dimethyl, S,Sxe2x80x2-diethyl, S,Sxe2x80x2-dipropyl, S,Sxe2x80x2-dibutyl, S,Sxe2x80x2-dipentyl, S,Sxe2x80x2-diphenyl, S,Sxe2x80x2-dibenzyl and S,Sxe2x80x2-diacetyl.
Cyclic Dithio Acetals and Ketals
Examples of acyclic dithio acetals and ketals include 1,3-dithiane, 1,3-dithiolane and 1,5-dihydro-3H-2,4-benzodithiepin.
Acyclic Monothio Acetals and Ketals
Examples of acyclic monothio acetals and ketals include O-trimethylsilyl-S-alkyl, O-methyl-S-alkyl or xe2x80x94S-phenyl and O-methyl-S-2-(methylthio)ethyl.
Cyclic Monothio Acetals and Ketals
Examples of cyclic monothio acetals and ketals include 1,3-oxathiolanes.
Miscellaneous Derivatives
O-Substituted Cyanohydrins
Examples of O-substituted cyanohydrins include O-acetyl, O-trimethylsilyl, O-1-ethoxyethyl and O-tetrahydropyranyl.
Substituted Hydrozones
Examples of substituted hydrazones include N,N-dimethyl and 2,4-dinitrophenyl.
Oxime Derivatives
Examples of oxime derivatives include O-methyl, O-benzyl and O-phenylthiomethyl.
Imines
Substitued Methylene Derivatives, Cyclic Derivatives
Examples of substituted methylene and cyclic derivatives include oxazolidines, 1-methyl-2-(1xe2x80x2-hydroxyalkyl)imidazoled, N,Nxe2x80x2-dimethylimidazolidines, 2,3-dihydro-1,3-benzothiazoles, diethylamine adducts, and methylaluminum bis(2,6-di-t-butyl-4-methylphenoxide)(MAD)complex.
Monoprotection of Dicarbonyl Compounds
Selectives Protection of xcex1- and xcex2-Diketones
Examples of selective protection of xcex1- and xcex2-diketones include enamines, enol acetates, enol ethers, methyl, ethyl, i-butyl, piperidinyl, morpholinyl, 4-methyl-1,3-dioxolanyl, pyrrolidinyl, bezyl, S-butyl, and trimethylsilyl.
Cyclic Ketals, Monothio and Dithio Ketals
Examples of cyclic ketals, monothio and dithio ketals include bismethylenedioxy derivatives and tetramethylbismethylenedioxy derivates.
Protecton for the Carboxyl Group
Esters
Substituted Methyl Esters
Examples of substituted methyl esters include 9-fluorenylmethyl, methoxymethyl, methylthiomethyl, tetrahydropyranyl, tetrahydrofuranyl, methoxyethoxymethyl, 2-(trimethylsilyl)ethoxymethyl, benzyloxymethyl, phenacyl, p-bromophenacyl, xcex1-methylphenacyl, p-methoxyphenacyl, carboxamidomethyl, and N-phthalimidomethyl.
2-Substituted Ethyl Esters
Examples of 2-substituted ethyl esters include 2,2,2-trichloroethyl, 2-haloethyl, xcfx89-chloroalkyl, 2-(trimethylsilyl)ethyl, 2-methylthioethyl, 1,3-dithianyl-2-methyl, 2-(p-nitrophenylsulfenyl)ethyl, 2-(p-toluenesulfonyl)ethyl, 2-(2xe2x80x2-pyridyl)ethyl, 2-(diphenylphosphino)ethyl, 1-methyl-1-phenylethyl, t-butyl, cyclopentyl, cyclohexyl, allyl, 3-buten-1-yl, 4-(trimethylsilyl)-2-buten-1-yl, cinnamyl, xcex1-methylcinnamyl, phenyl, p-(methylmercapto)phenyl and benzyl.
Substituted Benzyl Esters
Examples of substituted benzyl esters include triphenylmethyl, diphenylmethyl, bis(o-nitrophenyl)methyl, 9-anthrylmethyl, 2-(9,10-dioxo)anthrylmethyl, 5-dibenzosuberyl, 1-pyrenylmethyl, 2-(trifluoromethyl)-6-chromylmethyl, 2,4,6-trimethylbenzyl, p-bromobenzyl, o-nitrobenzyl, p-nitrobenzyl, p-methoxybenzyl, 2,6-dimethoxybenzyl, 4-(methylsulfinyl)benzyl, 4-sulfobenzyl, piperonyl, 4-picolyl and p-P-benzyl.
Silyl Esters
Examples of silyl esters include trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, i-propyldimethylsilyl, phenyldimethylsilyl and di-t-butylmethylsilyl.
Activated Esters
Examples of activated esters include thiols.
Miscellaneous Derivatives
Examples of miscellaneous derivatives include oxazoles, 2-alkyl-1,3-oxazolines, 4-alkyl-5-oxo-1,3-oxazolidines, 5-alkyl-4-oxo-1,3-dioxolanes, ortho esters, phenyl group and pentaaminocobalt(III) complex.
Stannyl Esters
Examples of stannyl esters include triethylstannyl and tri-n-butylstannyl.
Amides
Examples of amides include N,N-dimethyl, pyrrolidinyl, piperidinyl, 5,6-dihydrophenanthridinyl, o-nitroanilides, N-7-nitroindolyl, N-8-Nitro-1,2,3,4-tetrahydroquinolyl, and p-P-benzenesulfonamides.
Hydrazides
Examples of hydrazides include N-phenyl and N,Nxe2x80x2-diisopropyl.